Cytoplasmic chromatin triggers inflammation in senescence and cancer
By Zhixun Dou, Kanad Ghosh, Maria Grazia Vizioli, Jiajun Zhu, Payel Sen, Kirk J. Wangensteen, Johayra Simithy, Y. Lan, Yanping Lin, Zhuo Zhou and 14 more. Nature, 2017
1,182 citations recorded by the source corpus.
Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence, a form of terminal cell-cycle arrest associated with pro-inflammatory responses. The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS–STING (cyclic GMP–AMP synthase linked to stimulator of interferon genes) pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin–cGAS–STING pathway promotes the senescence-associated secretory phenotype in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.
Subfields: Immunology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/e0e058cb1ecfb654ecc2b2aff1d1d4638a291d76
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Immunology
- Tuo Li
- Zhijian J. Chen
- A. Ablasser
- Alejandra Hernandez-Segura
- Jesús Gil
- J. Nehme
- Domhnall McHugh
- M. Demaria
In Molecular Biology
- Zhijian J. Chen
- A. Ablasser
- Tuo Li
- Jesús Gil
- Alejandra Hernandez-Segura
- J. Nehme
- A. Alimonti
- J. Kohli
Citations in the corpus
- Senescence and aging: Causes, consequences, and therapeutic avenues (2018, positive): “Recently, sensing of cytoplasmic chromatin by the cGAS/STI NG pathway has been suggested as a trigger for SASP induction (Dou et al., 2017; Glück et al., 2017).”
- Hallmarks of Cellular Senescence. (2018, positive): “The major trigger for NF-kB activation is the DDR, but more recently the cGAS/STING pathway (see the section ‘Nuclear Changes’) has also been implicated [54,55].”
- Aging and aging-related diseases: from molecular mechanisms to interventions and treatments (2022, background): “During cellular senescence, loss of the nuclear membrane protein Lamin B17,11,12 leads to impaired integrity of the nuclear envelope, causing chromatin fragmentcontaining nuclear membranes to enter the cytoplasm as cytoplasmic chromatin fragments (CCF).(36) Further studies revealed that in senescent”
- The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer (2018, methodology): “Recent research has provided strong evidence that cGAS also has an essential role in promoting cellular senescence (Dou et al., 2017; Glück et al., 2017; Yang et al., 2017).”
- LINE-1 derepression in senescent cells triggers interferon and inflammaging (2019, neutral): “Cytoplasmic DNA can originate from several sources, such as mtDNA released from stressed mitochondria 28 or cytoplasmic chromatin fragments (CCF) released from damaged nuclei 29,30 .”